The possibility that the cyclic nucleotides, cyclic AMP and cyclic GMP, may mediate the generation of slow postsynaptic potentials was investigated in sympathetic ganglia of the bullfrog, using the sucrose gap technique. The administration of cyclic GMP, cyclic AMP, and their derivatives had no significant effect on membrane potential. The administration of theophylline (5 mM), an inhibitor of phosphodiesterase - the catabolic enzyme for cyclic nucleotides produced a depolarization of the membrane and an increase in membrane conductance. The muscarinic slow IPSP and the hyperpolarization produced by the administration of methacholine were both potentiated by theophylline. The muscarinic slow EPSP and the depolarization produced by the administration of methacholine were both reduced by theophylline. The noncholinergic late-slow EPSP was also reduced by theophylline. In calcium free Ringer, theophylline greatly enhanced the methacholine hyperpolarization, and the methacholine depolarization was virtually abolished. The results suggest that cyclic nucleotides are not directly involved in the generation of these slow postsynaptic potentials.